I 

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: (Richard Gebkin, PM 10, (703) 305-6701] 

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert "NA-Remove" and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green, i.e., "(insert 

company name]," with the information speciflc to your action. 

TEMPLATE: 

Gowan Company 

[Insert petition number] 

EPA has received a pesticide petition ((insert petition number]) from Gowan 

Company, LLC, P.O. Box 556 Yuma, AZ 85366 proposing, pursuant to section 4()8(d) 

of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 

CFR part 180. 

(Options (pick one) 

1. by establishing a tolerance for residues of 

Hexj'thiazox, (trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-

oxothiazolidine-3-carboxamide) in or on the raw agricultural commodit\' sugar beet, , . 

tops at 1.5 ppm, sugar beet, roots at 0.15 ppm and processed commodities, sugar 

beet, molasses at 0.21 ppm and sugar beet, dried pulp at 0.60 ppm. EPA has .****• 

determined that the petition contains data or information regarding the elements set forth * *" i • • 

in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency ,,,, * 

of the submitted data at this time or whether the data supports granting of the petition. *,,* 

Additional data may be needed before EPA rules on the petition. 

A. Residue Chemistry 

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1. Plant metabolism. The nature of the residues in plants is adeqnately 

understood for purposes of this tolerance petition. Metabolism studies in fruit crops, •* 

radish, tea and corn have been completed. The Agency has determined that the 

residues of concern are hex\'thiazox and its metabolites containing the 

(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiet\* calculated as the 

stoichiometric equivalent of hesy thiazox. 
2. Analytical method. The basic analytical method was previously reviewed by 

the Agency in association with the establishment of the current tolerances with 

registrations of multiple commodities. The methods used in a new sugar beet raw 

agricultural commodities study are described fully in the study report which is 

submitted concurrently with this petition. 

3. Magnitude of residues. A New Magnitude of the Residue data have been 

generated on sugar beet in EPA Regions 7 (one trial), 8 (one trial), 9 (one trial), 10 

(two trials), and 11 (one trial) to support regional registration. One sugar beet 

decline trial was conducted in EPA Regions 10. Six trials were conducted on sugar 

beet during the 2013 (three trials) and 2014 (three trials) growing seasons. The 

treated plots received one foliar broadcast application of Onager®lE Miticide at 

0.1875 lb ai/A (equal to 0.210 kg ai/ha) ± 5% applied 45 (±1) days before harvest 

(DBH). At Trial -06, an additional exaggerated 5x rate treated plot was established 

to generate sugar beet roots for the processing phase. This plot received one 5x rate 

application of Onager® IE Miticide at 0.9375 lb ai/A (equal to 1.05 kg ai/ha) ±5% 

applied 45 (±1) DBH. 

A single untreated control and duplicate treated RAC samples were harvested by 

hand at each location at normal crop maturity nominally 45 (44-46 day range) days 

after the application (DAA). At the decline site, additional treated RAC samples 

were collected 38, 59, and 66 DAA. 

The results from these trials show that after one application of Onager® IE Miticide 

at 0.1875 lb ai/A (0.210 kg ai/ha) ± 5% residues of hexv thiazox ranged from 0.208 to 

0.614 ppm (mean = 0.459 ppm ± 0.128) on twelve sugar beet top RAC samples 

collected 44-46 DAA and from <LOQ (0.00829) to 0.0597 ppm (mean = 0.0271 ppm 

± 0.0150) on twelve sugar beet root RAC samples collected 44-46 DAA. 

The results from the processing study show that after one 5x rate application of 

Onager® IE Miticide at 0.9359 lb ai/A (equal to 1.049 kg ai/ha), mean residues of 

hexj'thiazox in/on whole sugar beet roots collected immediately prior to processing;,,,;, 

was 0.311 ppm, collected 45 DAA. Mean residues of hexvthiazox in refined sugar, 

molasses, and dried pulp was 0.0425 ppm, 0.427 ppm, and 1.24 ppm, respectively. A,,,,* 

comparison of the hexj thiazox residues in the RAC with those in the processed • 

fractions (refined sugar, molasses, and dried pulp) indicated that the residues of 

hexvthiazox in sugar beet refined sngar, molasses, and dried pulp have **** •• 

concentration factors of approximately <lx, 1.4x, and 4.Ox, respectively. 

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B. Toxicological Profile 

1. Acute toxicity. A battery of acute toxicity studies places technical grade 

hexythiazox in Toxicity' Category IV for acute oral toxicity (LDso > 5,000 mg/kg), 

Categorv HI for acute dermal toxicitj' (LDso >5,000 mg/kg), Category HI for acute 

inhalation toxicity (LCso >2.0 mg/L), Category III for primary eye irritation 

(showed mild irritation (reddened conjunctiva) and Category IV for dermal 

irritation (non irritant). Hexythiazox is a non-sensitizer. 

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2. Genotoxicity. A number of mutagenicity studies were conducted. These are 

a mammalian erythrocyte micronucleus test [IVIRID 45480101], a mammalian cell 

forward gene mntation assay PVIRID 00155154], a rat primary hepatocyte 

unscheduled DNA synthesis assay [MRID 00156893], a clastogenic evaluation in an 

in vitro cytogenetic assay measuring chromosomal aberration in Chinese hamster 

ovary cells [MRID 00156894], and an Ames study with Salmonella [MRID 

44955710]. All these mutagenicity tests were negative. 

3. Reproductive and developmental toxicity. In a developmental toxicity study 

with rats [MRID 00147578], the fetotoxicity NOEL was 240 mg/kg/day, and the 

compound was not embryotoxic at the highest dose tested, 2160 mg/kg/day. In a 

developmental toxicity study with rabbits [MRID 00146555], no developmental 

toxicity' was observed at the highest dose tested, 1080 mg/kg/day. In a twogeneration reproduction study with rats [MRID 00147578 and 00151360], no 

reproductive effects were observed at 2400 ppm in the diet (^110 and >139 

mg/kg/day, males and females, respectively). It is concluded that the NOEL for 

developmental and reproductive effects is greater than 10 times the chronic NOEL. 

4. Subchronic toxicity. In a 1-month feeding study in dogs, the NOAEL was 

1.75 mg/kg/day and the LOAEL was 12.5 mg/kg/day, based on increased liver and 

adrenal weights. 

5. Chronic toxicity. In a 1-year feeding study in dogs, the NOAEL was 2.5 

mg/kg/day and the LOAEL was 12.5 mg/kg/day, based on increased alkaline 

phosphatase, increased adrenal and liver weights, and liver and adrenal lesions. In 

a carcinogenicity study in mice, the NOAEL was 36 mg/kg/day and the LOAEL was 

215 mg/kg/day. Effects were decreased bodweight in males and increased 

hepatocellular carcinomas and combined adenoma/carcinomas. 

In a chronic feeding/carcinogenicity study in rats, the NOAEL (systemic) was 26 

mg/kg/day and the LOAEL (systemic) was 180 mg/kg/day based on decreased body 

weight gain and increased liver weights in both sexes. 'im* 

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A 2009 report from the Cancer Assessment Review Committee (CARC) (September#,••••• 

02,2009, PC Code 128849, TXR 0055255) noted that the NOAEL of 2.5 mg/kg/day,* • • • • * *. • * 

from the one year toxicity study in dogs, used in establishing the chronic reference •**•*• 

dose (RfD) is approximately 65-fold lower than the low est dose (163 mg/kg/day) that' , 

induced tumors. Thus, the chronic RfD of 0.025 mg/kg/day would be protective of 

all chronic effects including potential carcinogenicity of hexythiazox. The CARC 

concluded that the evidence as a whole was not strong enough to warrant the use of,* !*• 

a linear low dose extrapolation model applied to the animal data (Ql*) for a 

quantitative estimation of human risk, as had been previously assessed in October 

16,1998, [63.FR55540]. 

6. Animal metabolism. The metabolism of hexvthiazox has been studied in 
goats, hens and rats. Metabolic pathways in the animal are similar to those in 

plants. 

7. Metabolite toxicology. There are no metabolites of toxicological concern 

based on a differential metabolism between plants and animals. 

8. Endocrine disruption. Information concerning possible endocrine effects of 

hex}'thiazox similar to effects produced by a naturally occurring estrogen, or other 

endocrine effects is available from the two-generation rat reproduction study, the 

rat and rabbit developmental studies and the rat and dog chronic studies. There is 

no evidence from these studies that hexj thiazox induces estrogenic or other 

endocrine effects. 

C. Aggregate Exposure 

1. Dietary exposure. Dietary Exposure from food. A dietary risk assessment 

for all registered crops has been completed by the Agency (Federal Register, July 

17, 2013, pages 42693-42699). 

1. Food. Acute Exposure. No acute endpoint has been identified in the 

toxicological studies for hexythiazox; therefore, a quantitative acute dietary 

exposure assessment is unnecessary . 

Chronic Exposure. The proposed regional tolerances for hexj thiazox in sugar beet 

will not add to dietary risk. A tier 1 chronic assessment shows employing tolerance 

residue values, the assumption of 100% crop treated and default processing factors 

shows that the maximally exposed subpopulation (children 1-2 years old) utilized 

93.1% of the RfD. 

ii. Drinking water. The Agency has previously used screening level surface 

water exposure models in dietaiy exposure analysis and risk assessment for 

hexythiazox in drinking water. Based on the Pesticide Root Zone Model /Exposure 

Analysis Modeling System (PRZM/EXAMS), the estimated drinking water 

concentration (EDWC) of hexy thiazox for chronic assessment was estimated to be * 

4.31 parts per billion (ppb). (Federal Register, Julv 17, 2013, pages 42693-42699) 

2. Non-dietary exposure. EPA has previously determined that potential 

residential exposures to hex^'thiazox are below levels of concern. **** •• 

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D. Cumulative Effects • 

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EPA has not found that hexy thiazox shares a common mechanism of toxicity* 

with any other substances. • 

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E. Safety Determination 

1. U.S. population. Acute risk. No adverse effect resulting from a single oral 

exposure to hexythiazox has been identified, thus hexythiazox is not expected to pose 
an acute risk. 

Short-and intermediate term risk. EPA has previously concluded that there are no 

short term or intermediate term risks of concern from exposure to hexjihiazox. 

Chronic risk. The proposed regional tolerances for hexythiazox in sugar beet will 

not add to dietary' risk. A tier 1 chronic assessment shows employing tolerance 

residue values, the assumption of 100% crop treated and default processing factors 

shows that the maximally exposed subpopulation (children 1-2 years old) utilized 

93.1% of the RfD. Chronic residential exposure to the residues of hexythiazox is not 

expected. 

2. Infants and children. EPA previously has determined that reliable data 

show the safety of infants and children would be adequately protected if the EQPA 

SF were reduced to IX. Based on these risk assessments, it can be concluded 

that there is a reasonable certainty that no harm will result to the general 

population, or to infants and children from aggregate exposure to hexythiazox 

residues. 

F. International Tolerances 

There are no international maximum residue levels established for 

hexythiazox on sugar beet. 

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